title: The anti-neurodegeneration drug clioquinol inhibits the aging-associated protein CLK-1.
abstract: The development of neurodegenerative diseases such as Alzheimer, Parkinson, and Huntington disease is strongly age-dependent. Discovering drugs that act on the high rate of aging in older individuals could be a means of combating these diseases. Reduction of the activity of the mitochondrial enzyme CLK-1 (also known as COQ7) slows down aging in Caenorhabditis elegans and in mice. Clioquinol is a metal chelator that has beneficial effects in several cellular and animal models of neurodegenerative diseases as well as on Alzheimer disease patients. Here we show that clioquinol inhibits the activity of mammalian CLK-1 in cultured cells, an inhibition that can be blocked by iron or cobalt cations, suggesting that chelation is involved in the mechanism of action of clioquinol on CLK-1. We also show that treatment of nematodes and mice with clioquinol mimics a variety of phenotypes produced by mutational reduction of CLK-1 activity in these organisms. These results suggest that the surprising action of clioquinol on several age-dependent neurodegenerative diseases with distinct etiologies might result from a slowing down of the aging process through action of the drug on CLK-1. Our findings support the hypothesis that pharmacologically targeting aging-associated proteins could help relieve age-dependent diseases.
authors.affiliation: Department of Biology, McGill University, Montráal, Quábec H3A 1B1, Canada and Chronogen Inc., Montráal, Quábec H1W 4A4, Canada.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biology, McGill University, Montráal, Quábec H3A 1B1, Canada and Chronogen Inc., Montráal, Quábec H1W 4A4, Canada.
authors.forename: Robyn
authors.initials: R
authors.lastname: Branicky
authors.affiliation: Department of Biology, McGill University, Montráal, Quábec H3A 1B1, Canada and Chronogen Inc., Montráal, Quábec H1W 4A4, Canada.
authors.forename: Zaruhi
authors.initials: Z
authors.lastname: Stepanyan
authors.affiliation: Department of Biology, McGill University, Montráal, Quábec H3A 1B1, Canada and Chronogen Inc., Montráal, Quábec H1W 4A4, Canada.
authors.forename: Melissa
authors.initials: M
authors.lastname: Carroll
authors.affiliation: Department of Biology, McGill University, Montráal, Quábec H3A 1B1, Canada and Chronogen Inc., Montráal, Quábec H1W 4A4, Canada.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Guimond
authors.affiliation: Department of Biology, McGill University, Montráal, Quábec H3A 1B1, Canada and Chronogen Inc., Montráal, Quábec H1W 4A4, Canada.
authors.forename: Abdelmadjid
authors.initials: A
authors.lastname: Hihi
authors.affiliation: Department of Biology, McGill University, Montráal, Quábec H3A 1B1, Canada and Chronogen Inc., Montráal, Quábec H1W 4A4, Canada.
authors.forename: Steve
authors.initials: S
authors.lastname: Hayes
authors.affiliation: Department of Biology, McGill University, Montráal, Quábec H3A 1B1, Canada and Chronogen Inc., Montráal, Quábec H1W 4A4, Canada. Electronic address: kevinmcbride@sympatico.ca.
authors.forename: Kevin
authors.initials: K
authors.lastname: McBride
authors.affiliation: Department of Biology, McGill University, Montráal, Quábec H3A 1B1, Canada and Chronogen Inc., Montráal, Quábec H1W 4A4, Canada. Electronic address: Siegfried.Hekimi@McGill.Ca.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Hekimi
mesh_terms: D000375:Aging / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007464:Clioquinol / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006899:Mixed Function Oxygenases; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism
chemical_list: C104339:CLK-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D002614:Chelating Agents; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D007464:Clioquinol; D006899:Mixed Function Oxygenases; C434481:Coq7 protein, mouse